These studies assessed efficacy and safety of a synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome (RDS) in premature rhesus. Surfactant was prepared consisting of phospholipids and a synthetic peptide modeled after surfactant protein b (sp-b). "Kl4-surfactant" contains a peptide having the sequence kllllkllll-kllllkllllk. This was selected because it mimics repeating stretches of hydrophobic residues with intermittent basic hydrophilic residues seen in SP-B. Kl4-surfactant was shown to have biophysical activity assessed as the ability to lower surface tension at an air-liquid interface in a pulsating bubble surfactometer. Thirty-four premature rhesus were treated with one dose of Kl4-surfactant within 3.3 Hours of birth. Arterial to alveolar oxygen partial pressure (a/a) ratio was found to rise from a pre-treatment level of 0.12 Q 0.006 (Mean q sem), indicative of rds, to 0.42 Q 0.021 At 12-13 hours post-treatment. Oxygenation improvement persisted throughout the study period, with a mean a/a at 22-23 hours of 0.47 Q 0.065. Gross and microscopic examination of the lungs and chest radiographs confirmed reversal of the atelectasis seen prior to treatment. Animals treated with 200 mg/kg showed faster, more consistent, and greater response than those treated with an average dose of 127 mg/kg. Twelve monkeys treated with ~200 mg/kg and followed 19-24 hours showed no evidence of toxicity as demonstrated by physiologic hematologic, biochemical, and pathologic data. The importance of the peptide in the synthetic surfactant was apparent from results obtained with a control group of nine premature monkeys treated with a non-peptide-containing surfactant (exosurf~); the a/a ratio of this group was 0.15 Q 0.03 At ten hours of age as compared with a value of 0.39 Q 0.04 For 18 comparable animals receiving kl4-surfactant. (Funded, in part, by the r.W. Johnson pharmaceutical research institute).